Our particular disease focus has been OCD for the past two decades. However, because OCD, like other anxiety/depression disorders exhibits high comorbidity with multiple disorders, comorbidity of neuropsychiatric disorders itself has been an additional special focus in consideration of our gene e environment and gene x gene studies in humans and indirectly in murine models. Our studies of Sert-targeted mice (and those of our collaborators and colleagues) have continued to show many similarities between the multiple phenotypes of mice with disrupted Sert gene function and those of humans who possess at least five functional SERT variants. [unreadable] Obsessive-compulsive disorder (OCD) is a severe, heritable condition with a lifetime prevalence of about two percent of world populations. The mode of inheritance is not well understood but is likely complex, involving multiple loci of small to moderate effect. Our laboratory has been active in studies of OCD and of its genetics for over 15 years, and in 2001 became one of the founding sites of a multi-center genetic study of OCD (P.I.: Dr. Gerald Nestadt of Johns Hopkins University). This study was approved via a competitive NIMH extramural grant application. [unreadable] Due to the accumulation of evidence supportive of genetic contributions to OCD, a series of association studies of candidate genes has been undertaken and reported in the literature, but only one, very small genome- wide scan of OCD had previously been reported. Our OCD genetic studies in the NIMH IRP contribute DNA and family evaluation data to this national multi-site, genome-wide study of OCD which described its methodology (Samuels et al., 2006) and reported the first results from a 10cM genome scan last year (Shugart et al., 2006). Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the 'broad' OCD definition, the strongest evidence for linkage was found on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. [unreadable] The collaborative group is currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping genes involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods. [unreadable] In addition, within the NIMH-IRP, exploratory analyses of DNA, clinical personality and other features of 300 OCD probands plus 700 of their relatives with or without OCD-related disorders are being used to assess the candidacy status of gene variants and to better define the familial OCD phenotype. [unreadable] In one such study, factor and cluster analysis of 70 OCD symptoms rated in each of the 317 patients with OCD from our Lab revealed a four factor grouping of symptoms which showed specific relationships to comorbid psychiatric disorders. Thus, Factor I (aggressive, sexual, religious and somatic obsessions, and checking compulsions) was broadly associated with comorbid anxiety disorder and depression; Factor II (obsessions of symmetry, and repeating, counting and ordering/arranging compulsions) with bipolar disorders and panic disorder/agoraphobia; and Factor III (contamination obsessions and cleaning compulsions) with eating disorders. Factors I and II were associated with early onset OCD. The frequent co-occurrence of OCD with other psychiatric disorders and the relatively specific association patterns between OCD symptom dimensions and comorbid disorders support the importance of OCD subtyping for genetic, treatment, and other research studies of this heterogeneous disorder. [unreadable] In a gene-based follow-up to this study, an association was replicated between the SERT 5HTTLPR functional polymorphism and the symmetry/counting/ordering (Factor II) dimension of OCD symptoms. In further studies of the SERT gene in OCD and related disorders such as Tourettes syndrome, the 5HTTLPR together with a newly-discovered SNP (rs25531) within it were found to be associated with OCD in both a case-control and a family-based trios study. Improved methods to genotype these and other variants in OCD were reported.[unreadable] The OCGS selected a sub-phenotype, hoarding, for secondary evaluation across the genome, based upon prior data that hoarding behaviors represented an OCD dimension that was familial in this sib-pair sample (Hasler et al., 2006) and might represent a distinct sub-phenotype worthy of further investigation (Frost et al., 1996; Samuels et al., 2006; LaSalle-Ricci et al., 2006; Zhang et al., 2002; Wheaton et al., 2007). When the OCGS OCD sample was limited to those with hoarding obsessions and compulsions (38% of the total sample), a strong genome-wide signal was found at 14p, with a LOD of 2.9, which increased further when only those OCD probands with two or more relatives with hoarding were included (LOD = 3.7) (Samuels et al., 2007). The original 3q signal found in the entire OCD group disappeared in a hoarding subsample, but was enhanced in the remaining larger non-hoarding group. This suggests that some heterogeneity in other OCD genetic studies may be contributed to by individuals with hoarding features. Earlier studies by our group and by others examining the clinical features of individuals with OCD revealed greater OCD severity, greater prevalence of comorbid disorders including social phobia and bipolar disorder, different personality features and relative insensitivity to both drug and behavioral therapy among hoarders (Frost et al., 1996; Samuels et al., 2006; LaSalle-Ricci et al., 2006; Wheaton et al., 2007; Cromer et al., 2006) [unreadable] A fairly strong genetic association between SERT and OCD, autism, ADHD, alcohol abuse and bipolar disorder has been demonstrated (Murphy et al., 2004). However, as in almost all candidate gene studies, there are some discrepant results. These neuropsychiatric disorders are not thought to be the result of any one gene but are, rather, a genetically complex configuration of multiple genes in multiple systems interacting together. Evidence of the involvement of SERT variants in these disorders raises the distinct possibility that serotonin-related genes that cause alterations in function of the serotonin system (such as TPH2, AADC, MAOA/B, HTR1A) and other serotonin receptor genes, as well as FEV, LMX1b, ITG3, BDNF and others might also be contributing to the disorder. However, less is known at present about functional variants in these genes and they have been less comprehensively studied. Their exploration seems to be a necessary next step in considering serotonergic involvement in these and related disorders.